Avian Papilloma and Squamous Cell Carcinoma: a Histopathological, Immunohistochemical and Virological study.

In this retrospective study, we describe the histopathological findings in seven papillomas and 45 squamous cell carcinomas (SCCs) from psittacine birds, raptors and domestic fowl. The age of affected birds ranged from 3 to 40 years, with median age significantly higher in psittacines (P = 0.014). The majority of tumours were located in the skin (24/52, 46.2%) or uropygial gland (10/52, 19.2%). Thirty of the SCCs (66.7%) were well differentiated and 15 (33.3%) were poorly-differentiated. SCCs exhibited a significantly higher degree of nuclear pleomorphism (P = 0.005) and a greater proportion were ulcerated (P = 0.001) compared with papillomas; however, there was no significant difference in mitotic count (MC) or inflammation score. The expression of cyclo-oxygenase (COX)-2 and E-cadherin was investigated by immunohistochemistry. The COX-2 total score (TS) was significantly higher in SCCs compared with papillomas (P = 0.002), but the difference between COX-2 TS of well- and poorly-differentiated SCCs was not significant. COX-2 labelling was predominantly cytoplasmic, but some tumours had concurrent membranous and/or perinuclear labelling. SCCs with membranous labelling had a significantly higher MC (P = 0.028). A significantly higher proportion of SCCs were negative for E-cadherin compared with papillomas (P = 0.042), but there was no significant difference between well- and poorly-differentiated SCCs. Fourteen papillomas and SCCs from psittacines were also tested by polymerase chain reaction for the presence of Psittacus erithacus papillomavirus 1 and Psittacid herpesvirus 1, but all samples tested negative. We demonstrate for the first time the expression of COX-2 and E-cadherin in avian tissues, and suggest that these markers may be useful in differentiating papillomas from SCCs, particularly when sample size is small.

An evaluation of methods for the isolation of nontuberculous mycobacteria from patients with cystic fibrosis, bronchiectasis and patients assessed for lung transplantation.

BACKGROUND: RGM medium is an agar-based, selective culture medium designed for the isolation of nontuberculous mycobacteria (NTM) from the sputum of patients with cystic fibrosis (CF). We evaluated RGM medium for the detection of NTM in patients with CF (405 samples), bronchiectasis (323 samples) and other lung diseases necessitating lung transplantation (274 samples). METHODS: In total, 1002 respiratory samples from 676 patients were included in the study. Direct culture on RGM medium, with incubation at two temperatures (30 °C and 37 °C), was compared with conventional culture of decontaminated samples for acid-fast bacilli (AFB) using both a solid medium (Löwenstein-Jensen medium) and a liquid medium (the Mycobacterial Growth Indicator Tube; MGIT). RESULTS: For all three patient groups, significantly more isolates of NTM were recovered using RGM medium incubated at 30 °C than by any other method (sensitivity: 94.6% vs. 22.4% for conventional AFB culture; P < 0.0001). Significantly more isolates of Mycobacterium abscessus complex were isolated on RGM at 30 °C than by AFB culture (sensitivity: 96.1% vs. 58.8%; P < 0.0001). The recovery of Mycobacterium avium complex was also greater using RGM medium at 30 °C compared to AFB culture (sensitivity: 83% vs. 70.2%), although this difference was not statistically significant and a combination of methods was necessary for optimal recovery (P = 0.21). CONCLUSIONS: In the largest study of RGM medium to date, we reaffirm its utility for isolation of NTM from patients with CF. Furthermore; we show that it also provides an effective tool for culture of respiratory samples from patients with bronchiectasis and other lung diseases.

Microscopic polyangiitis secondary to Mycobacterium abscessus in a patient with bronchiectasis: a case report.

BACKGROUND: Non-Tuberculous Mycobacterial-pulmonary disease (NTM-PD) is increasing in incidence and prevalence. Mycobacterium abscessus (M.abscessus) is a rapid growing multi-resistant NTM associated with severe NTM-PD requiring prolonged antibiotic therapy. Complications of therapy are common but reports on direct complications of active NTM-PD are rare. Vasculitis has been described as a rare complication of NTM-PD, most often in individuals with inherited immune defects. This case is the first to describe an ANCA positive vasculitide (Microscopic Polyangiitis) secondary to M.abscessus pulmonary disease. CASE PRESENTATION: A 70 year old female with bronchiectasis underwent a clinical decline associated with the growth of M.abscessus and was diagnosed with NTM-PD. Before treatment could be initiated she developed small joint arthralgia and a glove and stocking axonal loss sensorimotor neuropathy. Positive Perinuclear Anti-Neutrophil Cytoplasmic Antibodies (P-ANCA) and Myeloperoxidase-ANCA (MPO-ANCA) titres led to a diagnosis of microscopic polyangiitis. Further investigation revealed reduced interferon-gamma production but no other significant immune dysfunction. Dual treatment with immunosuppressive therapy (Corticosteroids/Cyclophosphamide) for vasculitis and antimicrobial therapy for M.abscessus NTM-PD was initiated. Clinical stability was difficult to achieve with reductions in immunosuppression triggering vasculitic flares. One flare led to retinal vein occlusion with impending visual loss requiring escalation in immunosuppression to Rituximab infusions. An increase in immunosuppression led to a deterioration in NTM-PD necessitating alterations to antibiotic regimes. Adverse effects including alopecia and Achilles tendonitis have further limited antibiotic choices resulting in a strategy of pulsed intra-venous therapy to stabilise NTM-PD. CONCLUSIONS: This is the first reported case of an ANCA positive vasculitis secondary to M.abscessus pulmonary disease. This rare but important complication had a significant impact on the patient adding to the complexity of an already significant disease and treatment burden. The potential role of reduced interferon-gamma production in this case highlights the importance of investigating immune function in those with mycobacterial infection and the intricate relationship between mycobacterial infection and immune dysfunction. Immune dysfunction caused by genetic defects or immunosuppressive therapy is a known risk factor for NTM-PD. Balancing immunosuppressive therapy with prolonged antimicrobial treatment is challenging and likely to become more common as the number of individuals being treated with biologics and immunosuppressive agents increases.

Misdiagnosis of diaphragmatic rupture in a trauma setting.

Distinguishing diaphragmatic eventration from rupture in the trauma setting can be a considerable challenge. We present a case involving a man suffering from chest pain and with a raised left hemidiaphragm on the chest radiograph after a motor vehicle injury. A review of the literature discusses the use of imaging modalities and subsequent surgical diagnostic procedures in the face of uncertainty.

UK guidance document: treatment of metastatic breast cancer.

Although there have been major improvements in the management of breast cancer, with a rapidly falling death rate despite an increasing incidence of the disease, metastatic breast cancer remains common and the cause of death in nearly 12 000 women annually in the UK. Numerous treatment options are available that either target the tumour or reduce the complications of the disease. Clinical decision making depends on knowledge of the extent and biology of the disease and available drug options, an understanding of the functional status, and also the wishes and expectations of the individual patient. In addition, the organisation of services and support of the patient are essential components of high-quality care. The National Institute for Health and Clinical Excellence (NICE) has produced guidelines for the treatment of advanced breast cancer, which in some areas have perhaps failed to appreciate the complexity of patient management. This guidance document aims to provide succinct practical advice on the treatment of metastatic breast cancer, highlight some limitations of the NICE guidelines, and provide suggestions for management where available data are limited.

Twice vs three-times daily antibiotics in the treatment of pulmonary exacerbations of cystic fibrosis.

BACKGROUND: Once daily dosing of aminoglycosides is widely used but is limited by the inconvenience of the slow infusion it requires and the associated three-times daily infusion of a beta-lactam. Twice daily tobramycin can be given as a slow IV bolus and may be more convenient. This study compares twice with three-times daily dosing of both tobramycin and ceftazidime. METHODS: This was a randomised, open-label, parallel group trial. CF patients presenting with an infective exacerbation were randomised to either twice or three-times daily ceftazidime and tobramycin. Markers of treatment efficacy and safety were measured in the two groups. The primary outcome measure was improvement in FEV1. RESULTS: 146 patients were randomised into the study. There was no significant difference in the two groups for improvement in FEV1% predicted (9.93% and 7.98% for twice daily and three-times daily respectively) and similar times to next exacerbation. There were no differences in the incidence of treatment failure, nephrotoxicity and ototoxicity. DISCUSSION: This study confirms that twice daily dosing of both tobramycin and ceftazidime is safe and effective and may be considered more convenient than current dosing schedules.

Impact of effective prevention and management of febrile neutropenia.

Chemotherapy-induced febrile neutropenia is costly in both financial and human terms. The associated costs can be reduced substantially through the development and implementation of national policies and locally agreed protocols for the prevention and management of febrile neutropenia. Patients, the NHS, healthcare professionals and the broader community all stand to benefit from a commitment to effective management of this common and predictable side effect of some chemotherapy regimens for early-stage breast cancer.

Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring.

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

Variations in radiation exposures of adults and children in the UK.

Members of the UK population receive radiation doses from a number of sources including cosmic radiation, from uranium, thorium and their decay products, particularly radon, and from medical sources. On average, members of the UK population receive an effective dose of about 200 mSv over their lifetime. This results in a risk of fatal cancer of about 1%. However, the radiation dose is not the same to all individuals. Some components give doses that vary systematically from one region to another. Doses may also vary greatly from one individual to another. The rate at which the dose is accumulated may vary as the individual ages. Different organs and tissues do not necessarily receive the same dose. This paper discusses these factors and attempts to quantify them. Cosmic rays deliver doses which vary little across the body or between individuals. Terrestrial gamma rays also deliver more or less uniform whole-body doses, but the difference between individuals can be greater. Radionuclides in food deliver doses which vary both across the body and between individuals. These variations are even more marked in the case of doses from radon and from medical exposures.

Review of the radiation exposure of the UK population.

Since 1974 the National Radiological Protection Board (now the Radiation Protection Division of the Health Protection Agency) has produced reviews of the levels of exposure to ionising radiation in the UK, from sources of natural and artificial origin. The latest review (Watson et al 2005 Ionising Radiation Exposure of the UK Population: 2005 Review HPA-RPD-001 (Chilton: HPA-RPD)) in the series gives estimates of annual doses based predominantly on data collected for the years 2001-2003. The overall average annual dose is rounded to 2.7 mSv, and the average annual dose from natural radiation is found to be 2.2 mSv. The overall average annual dose is slightly increased over that found in the previous, 1999, review. This increase is mainly due to a larger contribution from medical irradiation.

Dietzia strain X: a newly described Actinomycete isolated from confluent and reticulated papillomatosis.

Confluent and reticulated papillomatosis (CRP) is a rare skin disorder. To date its aetiology remains uncertain. The possibility of an infectious aetiology has been supported by case reports of therapeutic response to antibiotic therapy. We have isolated and identified a previously unknown Dietzia strain, an Actinomycete, from skin scrapings of a 17-year-old boy with CRP. We propose that this organism may be the aetiological agent of CRP. Further investigations are necessary to determine the potential role of this Actinomycete in the pathogenesis of CRP.

Preliminary results and complications following limited open reduction and percutaneous screw fixation of displaced fractures of the acetabulum.

Twenty-four patients underwent attempted closed or limited open reduction of displaced acetabular fractures. If reduction was successful, the fractures were stabilized with percutaneous screws. Group 1 was composed of elderly patients with complex fractures and radiographic findings that were felt to be predictive of post-traumatic arthritis. In these patients, percutaneous screw fixation was used to improve fracture anatomy, allow mobilization and total hip replacement later, if necessary. In group 1, anatomical reduction was not felt to be a necessity. Group 2 was composed of young patients with simple fracture types. For group 2, anatomical reduction was the goal. In 23/24 patients, closed or limited open reduction was successful. In group 1, maximum displacement averaged 10 mm preoperatively, 3 mm postoperatively. In group 2, maximum displacement averaged 7 mm preoperatively, 1 mm postoperatively. One elderly patient was lost to follow-up and one died, leaving 21 patients with an average follow-up of 12 months. All the fractures healed. One patient had a transient femoral nerve palsy, and two elderly patients had minor losses of reduction due to unprotected ambulation after surgery. Five of the elderly patients have gone on to total hip arthroplasty. The average Harris Hip scores in groups 1 and 2 were 85 and 96, respectively.

A prospective evaluation of the clinical utility of the lower-extremity injury-severity scores.

BACKGROUND: High-energy trauma to the lower extremity presents challenges with regard to reconstruction and rehabilitation. Failed efforts at limb salvage are associated with increased patient mortality and high hospital costs. Lower-extremity injury-severity scoring systems were developed to assist the surgical team with the initial decision to amputate or salvage a limb. The purpose of the present study was to prospectively evaluate the clinical utility of five lower-extremity injury-severity scoring systems. METHODS: Five hundred and fifty-six high-energy lower-extremity injuries were prospectively evaluated with use of five injury-severity scoring systems for lower-extremity trauma designed to assist in the decision-making process for the care of patients with such injuries. Four hundred and seven limbs remained in the salvage pathway six months after the injury. The sensitivity, specificity, and area under the receiver operating characteristic curve were calculated for the Mangled Extremity Severity Score (MESS); the Limb Salvage Index (LSI); the Predictive Salvage Index (PSI); the Nerve Injury, Ischemia, Soft-Tissue Injury, Skeletal Injury, Shock, and Age of Patient Score (NISSSA); and the Hannover Fracture Scale-97 (HFS-97) for ischemic and nonischemic limbs. The scores were analyzed in two ways: including and excluding limbs that required immediate amputation. RESULTS: The analysis did not validate the clinical utility of any of the lower-extremity injury-severity scores. The high specificity of the scores in all of the patient subgroups did confirm that low scores could be used to predict limb-salvage potential. The converse, however, was not true. The low sensitivity of the indices failed to support the validity of the scores as predictors of amputation. CONCLUSIONS: Lower-extremity injury-severity scores at or above the amputation threshold should be cautiously used by a surgeon who must decide the fate of a lower extremity with a high-energy injury.

Characterization of patients with high-energy lower extremity trauma.

PURPOSE: (a) to report the demographic, socioeconomic, behavioral, social, and vocational characteristics of patients enrolled in a study to examine outcomes after high-energy lower extremity trauma (HELET) and to compare them with the general population; (b) to determine whether characteristics of patients undergoing limb salvage versus amputation after HELET are significantly different from each other. DESIGN AND STUDY POPULATION: A prospective study of 601 patients admitted with high-energy lower extremity trauma to eight Level I trauma centers. PROCEDURES: Patients were evaluated during the initial hospitalization. They are being followed up for 24 months postinjury. Study patients are compared with the general population by using census information, population survey data, and published norms. Characteristics of patients undergoing limb salvage versus amputation are also compared. RESULTS: Most patients were male (77 percent), white (72 percent), and between the ages of twenty and forty-five years (71 percent). Seventy percent graduated from high school (compared with 86 percent nationally) (p < 0.05). One fourth lived in households with incomes below the federal poverty line, compared with 16 percent nationally (p < 0.05). The percentage with no health insurance (38 percent) was also higher than in the general population (20 percent) (p < .05). The percentage of heavy drinkers was over two times higher than reported nationally (p < 0.01). Study patients were slightly more neurotic and extroverted and less open to new experiences. When patient characteristics were compared for those undergoing amputation versus limb salvage, no significant differences were found among any of the variables (p > 0.05). CONCLUSION: In conclusion, LEAP patients differ in important ways from the general population. However, the decision to amputate verus reconstruct does not appear to be significantly influenced by patient characteristics.

Polymorphism of human mucin genes in chest disease: possible significance of MUC2.

Most of the genes that encode epithelial mucins are highly polymorphic due to variations in the length of domains of tandemly repeated (TR) coding sequence, the part of the apomucin that is heavily glycosylated. We report here for the first time a difference in the distribution of MUC TR length alleles in chest disease. We examined the distribution of the length alleles of those MUC genes whose expression we have confirmed in the bronchial tree in an age- and sex-matched series of 50 pairs of atopic patients with and without asthma. There was no significant difference in the distribution of alleles of MUC1, MUC4, MUC5AC, and MUC5B. MUC2, however, showed a highly significant difference in distribution. The atopic, nonasthmatic individuals showed an allele distribution that was very different from all our other patient and control groups, this group showing a longer mean allele length. The observations suggest that longer MUC2 alleles may help protect atopic individuals from developing asthma, though the effect may be due to a linked gene. The biological significance of this variation with respect to susceptibility to asthma will merit further investigation, and it will also be important to substantiate this finding on an independent data set.

Expression of epidermal growth factor and its receptor in cirrhotic liver disease.

Polypeptide growth factors, including epidermal growth factor (EGF), play a central role in regulating hepatocyte growth both in vivo and in primary culture. To characterize EGF gene expression in the pathogenesis of regenerative cirrhotic fibrosis, we employed biotinylated antisense oligonucleotide probes to localize hepatic mRNA transcripts in situ. In control tissue and regenerative hepatic nodules, EGF receptor (EGFR) mRNA transcripts were expressed constitutively. In contrast, oligonucleotide probes targeting the human EGF coding region showed that EGF transcription was extremely low in control liver but was highly elevated and localized to regenerative hepatic nodules and bile duct epithelia of cirrhotic liver. To determine whether EGF mRNA accumulation accompanied a comparable increase in the EGF peptide, we performed immunohistochemistry using an antibody specific for the nonprocessed peptide aminoterminus. We observed that positive localized EGF staining paralleled its mRNA transcript. These results indicate that EGF upregulation is a characteristic of cirrhotic liver disease and suggest that persistent de novo ligand synthesis and its signaling contribute to an autocrine-mediated hepatocyte proliferation within the regenerative nodule.

Toxicity of high-activity 111In-Octreotide therapy in patients with disseminated neuroendocrine tumours.

Disseminated neuroendocrine tumours are difficult to treat and are generally not responsive to radiotherapy or chemotherapy. Nuclear medicine techniques using a radiolabelled somatostatin analogue, 111In-Octreotide, have been used for the diagnosis of neuroendocrine tumours. It has been suggested that high activities of such an agent may have a therapeutic effect. The aims of this study were to assess toxicity and to determine if there had been evidence of efficacy. Eight patients with known disseminated neuroendocrine tumours were enrolled in the study; six had carcinoid tumours, one had a medullary cell carcinoma of the thyroid and one patient had a malignant gastrinoma. Between 1.3 and 4.6 GBq of 111In-Octreotide were administered to each patient for up to five administrations over 12 months. A total of 23 administrations were given. Tests of vital signs, renal, liver and endocrine function as well as haematological markers were taken before and after treatment. The treatment was well tolerated with only one patient suffering from a sensation of flushing during the infusion but no changes in vital sings. There was a transient (up to 48 h) drop in circulating lymphocytes in four patients and platelets in two patients; no supportive therapy was needed. One patient with severe renal impairment had a slight reduction in glomerular filtration rate. We conclude that high-activity 111In-Octreotide is well tolerated with low toxicity and can be considered for use in patients with disseminated neuroendocrine tumours. Further work is now being performed to assess efficacy.

The localization and interactions of huntingtin.

Huntingtin was localized by using a series of antibodies that detected different areas of the protein from the immediate N-terminus to the C-terminal region of the protein. The more C-terminal antibodies gave a cytoplasmic localization in neurons of the brain in controls and cases of Huntington's disease (HD). The N-terminal antibody, however, gave a distinctive pattern of immunoreactivity in the HD brain, with marked staining of axon tracts and white matter and the detection of densely staining intranuclear inclusions. This implies some processing differences between mutated and normal huntingtin. We have also localized two interacting proteins, cystathionine beta-synthase and the nuclear receptor co-repressor (N-CoR), in brain. Cystathionine beta-synthase was not relocalized in HD brain, but the N-CoR was excluded from neuronal nuclei in HD brain, and a further protein that exists in the same repression complex, mSin3, was similarly excluded. We conclude that the co-repressor might have a part in HD pathology.

Elevated immunoglobulin E (IgE) levels in children with exposure to environmental lead.

Lead has been reported to be an immunosuppressive agent in animal systems at levels far below those recognized as overtly toxic. Little data exist on lead's effects on the human immune system, especially in young children who are at greatest risk for exposure to this environmental hazard. The effects of environmental lead exposure on the human immune system were examined in a population of young children, age 9 months-6 years, from the urban population of Springfield-Greene County, Missouri. Reported here are data from 279 children with blood lead levels ranging from 1 to 45 microg/dl. White blood cell populations have been enumerated and examined for cell surface expression of activation markers. Serum has been analyzed for IgE, specific titers to Rubella vaccine, sCD25 (the soluble form of the IL2 receptor), sCD27 (the soluble form of the lymphocyte specific member of the tumor necrosis factor receptor family), and IL4 (the cytokine interleukin 4). Variation of these assays with age of the child was considered in statistical analysis of data. A statistically significant relationship of IgE and blood lead level was found in this population; as blood lead (PbB) level increases, IgE level increases. No other statistically significant differences between risk categories or other associations with blood lead level were found. The exact mechanism for this apparent stimulus of IgE-producing B cells remains to be elucidated. The development of allergic symptoms is often preceded by an increase in IgE. These data indicate that ingested lead could play a role in this process by stimulating IgE production.